Switch from type II to I Fas/CD95 death signaling on in vitro culturing of primary hepatocytes

Fas/CD95-induced apoptosis of hepatocytes in vivo proceeds through the so-called type II pathway, requiring the proapoptotic BH3-only Bcl-2 family member Bid for mitochondrial death signaling. Consequently, Bid-deficient mice are protected from anti-Fas antibody injection induced fatal hepatitis. We report the unexpected finding that freshly isolated mouse hepatocytes, cultured on collagen or Matrigel, become independent of Bid for Fas-induced apoptosis, thereby switching death signaling from type II to type I. In such in vitro cultures, Fas ligand (FasL) activates caspase-3 without Bid cleavage, Bax/Bak activation or cytochrome c release, and neither Bid ablation nor Bcl-2 overexpression is protective. The type II to type I switch depends on extracellular matrix adhesion, as primary hepatocytes in suspension die in a Bid-dependent manner. Moreover, the switch is specific for FasL-induced apoptosis as collagen-plated Bid-deficient hepatocytes are protected from tumor necrosis factor alpha/actinomycin D (TNFalpha/ActD)-induced apoptosis. Conclusion: Our data suggest a selective crosstalk between extracellular matrix and Fas-mediated signaling that favors mitochondria-independent type I apoptosis induction.

Publication and non-publication of clinical trials: longitudinal study of applications submitted to a research ethics committee

BACKGROUND: Not all clinical trials are published, which may distort the evidence that is available in the literature. We studied the publication rate of a cohort of clinical trials and identified factors associated with publication and nonpublication of results. METHODS: We analysed the protocols of randomized clinical trials of drug interventions submitted to the research ethics committee of University Hospital (Inselspital) Bern, Switzerland from 1988 to 1998. We identified full articles published up to 2006 by searching the Cochrane CENTRAL database (issue 02/2006) and by contacting investigators. We analyzed factors associated with the publication of trials using descriptive statistics and logistic regression models. RESULTS: 451 study protocols and 375 corresponding articles were analyzed. 233 protocols resulted in at least one publication, a publication rate of 52%. A total of 366 (81%) trials were commercially funded, 47 (10%) had non-commercial funding. 346 trials (77%) were multi-centre studies and 272 of these (79%) were international collaborations. In the adjusted logistic regression model non-commercial funding (Odds Ratio [OR] 2.42, 95% CI 1.14-5.17), multi-centre status (OR 2.09, 95% CI 1.03-4.24), international collaboration (OR 1.87, 95% CI 0.99-3.55) and a sample size above the median of 236 participants (OR 2.04, 95% CI 1.23-3.39) were associated with full publication. CONCLUSIONS: In this cohort of applications to an ethics committee in Switzerland, only about half of clinical drug trials were published. Large multi-centre trials with non-commercial funding were more likely to be published than other trials, but most trials were funded by industry.

Individual versus standard quality of life assessment in a phase II clinical trial in mesothelioma patients: feasibility and responsiveness to clinical changes

In patients with malignant pleural mesothelioma undergoing a multimodality therapy, treatment toxicity may outweigh the benefit of progression-free survival. The subjective experience across different treatment phases is an important clinical outcome. This study compares a standard with an individual quality of life (QoL) measure used in a multi-center phase II trial.

Acute lower gastrointestinal hemorrhage: minimally invasive management with microcatheter embolization

PURPOSE: To evaluate the efficacy of superselective embolization therapy in the management of acute lower gastrointestinal (LGI) hemorrhage, including any bleeding distal to the ligament of Treitz. MATERIALS AND METHODS: Between June and August 2007, 20 patients with acute LGI bleeding underwent superselective transcatheter arterial embolization (TAE) at the authors' institution. The bleeding had different causes. All patients were treated with use of microcatheters. The following embolic agents were used: microcoils (n = 16), polyvinyl alcohol (PVA) particles (n = 2), and a combination of microcoils and PVA particles (n = 2). Outcome measures included technical success (complete cessation of bleeding as documented at completion angiography), clinical success (resolution of signs or symptoms of LGI bleeding within 30 days after TAE), and the rate of major and minor complications. RESULTS: The identified bleeding sources were as follows: jejunal branch, branch of middle colic artery, branch of ileocolic artery, ileal branch, branch of left colic artery, branch of sigmoid artery, branch of the superior rectal artery, and branch of the middle rectal artery. Technical success with effective control of active bleeding was achieved in all patients (100%). Clinical success attributed to TAE was documented in 18 of the 20 patients (90%). Major complications included death due to pulmonary embolism, heart infarction, and multiorgan failure in the 3rd week after TAE; a procedure-related colonic infarction occurred in one patient. A minor complication occurred in one patient who developed a groin hematoma. CONCLUSIONS: Superselective embolization may be used for effective, minimally invasive control of acute LGI bleeding.

Oral diacetylmorphine (heroin) yields greater morphine bioavailability than oral morphine: bioavailability related to dosage and prior opioid exposure

AIMS: In the Swiss heroin substitution trials, patients are treated with self-administered diacetylmorphine (heroin). Intravenous administration is not possible in patients that have venosclerosis. Earlier studies have demonstrated that oral diacetylmorphine may be used, although it is completely converted to morphine presystemically. Morphine bioavailability after high-dose oral diacetylmorphine is considerably higher than would be predicted from low-dose trials. The aim was to investigate whether the unexpectedly high bioavailability is due to a difference in the drug examined, and whether it depends on previous exposure or on dose. METHODS: Opioid-naive healthy volunteers and dependent patients from the Swiss heroin trials (n = 8 per group) received low doses of intravenous and oral deuterium-labelled morphine and diacetylmorphine, respectively. Patients also received a high oral diacetylmorphine dose. RESULTS: The maximum plasma concentration (C(max)) of morphine was twofold higher after oral diacetylmorphine than after morphine administration in both groups. However, morphine bioavailability was considerably higher in chronic users [diacetylmorphine 45.6% (95% confidence interval 40.0, 51.3), morphine 37.2% (30.1, 44.3)] than in naive subjects [diacetylmorphine 22.9% (16.4, 29.4), morphine 23.9% (16.5, 31.2)] after low oral doses (48.5 micromol) of either diacetylmorphine or morphine. Morphine clearance was similar in both groups. Moreover, oral absorption of morphine from diacetylmorphine was found to be dose dependent, with bioavailability reaching 64.2% (55.3, 73.1) for high diacetylmorphine doses (1601 micromol). CONCLUSIONS: Oral absorption of opioids is substance-, dose- and patient collective-dependent, suggesting that there may be a saturation of first-pass processes, the exact mechanism of which is not yet understood.

Oral heroin in opioid-dependent patients: pharmacokinetic comparison of immediate and extended release tablets

In diacetylmorphine prescription programs for heavily dependent addicts, diacetylmorphine is usually administered intravenously, but this may not be possible due to venosclerosis or when heroin abuse had occurred via non-intravenous routes. Since up to 25% of patients administer diacetylmorphine orally, we characterised morphine absorption after single oral doses of immediate and extended release diacetylmorphine in 8 opioid addicts. Plasma concentrations were determined by liquid chromatography-mass spectrometry. Non-compartmental methods and deconvolution were applied for data analysis. Mean (+/-S.D.) immediate and extended release doses were 719+/-297 and 956+/-404 mg, with high absolute morphine bioavailabilities of 56-61%, respectively. Immediate release diacetylmorphine caused rapid morphine absorption, peaking at 10-15 min. Morphine absorption was considerably slower and more sustained for extended release diacetylmorphine, with only approximately 30% of maximal immediate release absorption being reached after 10 min and maintained for 3-4h, with no relevant food interaction. The relative extended to immediate release bioavailability was calculated to be 86% by non-compartmental analysis and 93% by deconvolution analysis. Thus, immediate and extended release diacetylmorphine produce the intended morphine exposures. Both are suitable for substitution treatments. Similar doses can be applied if used in combination or sequentially.

HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death

HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin-1 and Atg5. Suppression of Beclin-1 and Atg5 improved the survival of HAMLET-treated tumor cells and inhibited the increase in granular LC3-GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET-induced tumor cell death.

Prevalence of halitosis in the population of the city of Bern, Switzerland: a study comparing self-reported and clinical data

Epidemiological data on halitosis are rare. In this study we evaluated the prevalence of halitosis in the population of the city of Bern, Switzerland, using a standardized questionnaire and clinical examination. First of all, a standardized questionnaire was filled out by all 419 participants. In the clinical examination, 'objective' values for halitosis were gathered through two different organoleptic assessments and by the measurement of volatile sulfur compounds (VSC). Additionally, tongue coating and the modified periodontal screening index (PSI) were evaluated for each participant. The questionnaire revealed that 32% of all subjects sometimes or often experienced halitosis. The organoleptic evaluation (grade 0-5) identified 48 persons with grade 3 and higher. Measurement of VSC identified 117 subjects (28%) with readings of >or= 75 parts per billion (ppb). Tongue coating, modified PSI, and smoking were significantly associated with higher organoleptic scores, and tongue coating and smoking were associated with higher VSC values. For about one-third of the Bernese city population, halitosis seems to pose an oral health problem. Only a weak correlation between self-reported halitosis and either organoleptic or VSC measurements could be detected.

Is a change in patient-reported dysphagia after induction chemotherapy in locally advanced esophageal cancer a predictive factor for pathological response to neoadjuvant chemoradiation?

GOALS OF WORK: In patients with locally advanced esophageal cancer, only those responding to the treatment ultimately benefit from preoperative chemoradiation. We investigated whether changes in subjective dysphagia or eating restrictions after two cycles of induction chemotherapy can predict histopathological tumor response observed after chemoradiation. In addition, we examined general long-term quality of life (QoL) and, in particular, eating restrictions after esophagectomy. MATERIALS AND METHODS: Patients with resectable, locally advanced squamous cell- or adenocarcinoma of the esophagus were treated with two cycles of chemotherapy followed by chemoradiation and surgery. They were asked to complete the EORTC oesophageal-specific QoL module (EORTC QLQ-OES24), and linear analogue self-assessment QoL indicators, before and during neoadjuvant therapy and quarterly until 1 year postoperatively. A median change of at least eight points was considered as clinically meaningful. MAIN RESULTS: Clinically meaningful improvements in the median scores for dysphagia and eating restrictions were found during induction chemotherapy. These improvements were not associated with a histopathological response observed after chemoradiation, but enhanced treatment compliance. Postoperatively, dysphagia scores remained low at 1 year, while eating restrictions persisted more frequently in patients with extended transthoracic resection compared to those with limited transhiatal resection. CONCLUSIONS: The improvement of dysphagia and eating restrictions after induction chemotherapy did not predict tumor response observed after chemoradiation. One year after esophagectomy, dysphagia was a minor problem, and global QoL was rather good. Eating restrictions persisted depending on the surgical technique used.

Postmortem multislice computed tomography and magnetic resonance imaging of odontoid fractures, atlantoaxial distractions and ascending medullary edema

Non-invasive imaging methods are increasingly entering the field of forensic medicine. Facing the intricacies of classical neck dissection techniques, postmortem imaging might provide new diagnostic possibilities which could also improve forensic reconstruction. The aim of this study was to determine the value of postmortem neck imaging in comparison to forensic autopsy regarding the evaluation of the cause of death and the analysis of biomechanical aspects of neck trauma. For this purpose, 5 deceased persons (1 female and 4 male, mean age 49.8 years, range 20-80 years) who had suffered odontoid fractures or atlantoaxial distractions with or without medullary injuries, were studied using multislice computed tomography (MSCT), magnetic resonance imaging (MRI) and subsequent forensic autopsy. Evaluation of the findings was performed by radiologists, forensic pathologists and neuropathologists. The cause of death could be established radiologically in three of the five cases. MRI data were insufficient due to metal artefacts in one case, and in another, ascending medullary edema as the cause of delayed death was only detected by histological analysis. Regarding forensic reconstruction, the imaging methods were superior to autopsy neck exploration in all cases due to the post-processing possibilities of viewing the imaging data. In living patients who suffer medullary injury, follow-up MRI should be considered to exclude ascending medullary edema.